Phylogeography of Japanese encephalitis virus: genotype is associated with climate

Abstract

The circulation of vector-borne zoonotic viruses is largely determined by the overlap in the geographical distributions of virus-competent vectors and reservoir hosts. What is less clear are the factors influencing the distribution of virus-specific lineages. Japanese encephalitis virus (JEV) is the most important etiologic agent of epidemic encephalitis worldwide, and is primarily maintained between vertebrate reservoir hosts (avian and swine) and culicine mosquitoes. There are five genotypes of JEV: GI-V. In recent years, GI has displaced GIII as the dominant JEV genotype and GV has re-emerged after almost 60 years of undetected virus circulation. JEV is found throughout most of Asia, extending from maritime Siberia in the north to Australia in the south, and as far as Pakistan to the west and Saipan to the east. Transmission of JEV in temperate zones is epidemic with the majority of cases occurring in summer months, while transmission in tropical zones is endemic and occurs year-round at lower rates. To test the hypothesis that viruses circulating in these two geographical zones are genetically distinct, we applied Bayesian phylogeographic, categorical data analysis and phylogeny-trait association test techniques to the largest JEV dataset compiled to date, representing the envelope (E) gene of 487 isolates collected from 12 countries over 75 years. We demonstrated that GIII and the recently emerged GI-b are temperate genotypes likely maintained year-round in northern latitudes, while GI-a and GII are tropical genotypes likely maintained primarily through mosquito-avian and mosquito-swine transmission cycles. This study represents a new paradigm directly linking viral molecular evolution and climate.

Figure 1. Geographical distribution of the JEV sequences included in this study according to country of collection.

The coloring of the chart corresponds to the map and shows the relative proportions of viral sequences sampled from each country according to genotype. Of note, GI viruses have also been isolated in India, Laos and Malaysia, GII viruses have also been isolated in Papua New Guinea and Thailand, and GIII viruses have also been isolated in Malaysia, Myanmar, Nepal, the Philippines, the former Soviet Union and Thailand. These viruses were not included in this study, as the E gene of these viruses has not been sequenced. The estimated dates (95% HPD interval) and locations for the MRCA of JEV, as well as its five genotypes are also shown.

Figure 2. Geographical distribution of the JEV sequences included in this study according to climate of collection.

The coloring of the chart corresponds to the map and shows the relative proportions of viral sequences sampled from each climate according to genotype. The estimated dates (95% HPD interval) and location for the MRCA of JEV, as well as its five genotypes are also shown.

Figure 3. Country Bayesian MCC phylogeny of the JEV sequences.

GI-V are represented to the right of the tree. Branch tips correspond to the date of collection of each of the virus isolates from which JEV sequence information was derived. Branch lengths correspond to lengths of time (in years), as measured by the scale underneath the tree. Terminal branches are colored according to the sampling location of the taxon at the tip, while internal braches are colored according to the most probable location of their child node. The branch colors correspond to those used in the map and legend. The numbers to the upper-left of the nodes correspond to the country phylogeographic analysis date presented in Table 2 and the numbers to the lower-left of the nodes are posterior probability values.

Figure 4. Climate Bayesian MCC phylogeny of the JEV sequences.

GI-V are represented to the right of the tree. Branch tips correspond to the date of collection of each of the virus isolates from which JEV sequence information was derived. Branch lengths correspond to lengths of time (in years), as measured by the scale underneath the tree. Terminal branches are colored according to the sampling location of the taxon at the tip, while internal braches are colored according to the most probable location of their child node. The branch colors correspond to those used in the map and legend. The numbers to the upper-left of the nodes correspond to the country phylogeographic analysis date presented in Table 3 and the numbers to the lower-left of the nodes are posterior probability values.